title: Disease-modifying effect of ASP3258, a novel phosphodiesterase type 4 inhibitor, on subchronic cigarette smoke exposure-induced lung injury in guinea pigs.
abstract: ASP3258 is a novel, orally active, selective phosphodiesterase (PDE) 4 inhibitor which has an improved therapeutic window over second generation compounds such as roflumilast and cilomilast. Here, we investigated the effect of ASP3258 on cigarette smoke exposure-induced lung injury in guinea pigs, a well-defined model for chronic obstructive pulmonary disease (COPD). COPD-like lung injury was induced by repeated cigarette smoke exposure (10 cigarettes/day, 5 days/week, for 4 weeks). Orally administered ASP3258 (0.3, 1, and 3mg/kg) dose-dependently suppressed pulmonary accumulation of mononuclear cells and neutrophils, and the inhibitory effect of ASP3258 (1mg/kg) was almost the same as that of roflumilast (1mg/kg). In contrast, a glucocorticoid prednisolone (10mg/kg, p.o.) did not show any effect. Histological examination revealed that ASP3258 treatment significantly inhibited infiltration of neutrophils and macrophages into either or both alveolar or peribronchiolar areas, as well as hyperplastic and squamous metaplastic changes of epithelium in the bronchi. Decreasing trends in histological scores for accumulation of lymphocytes in the alveoli and alveolar wall thickening were also observed in ASP3258-treated animals. Further, ASP3258 attenuated augmentation of matrix metalloproteinase-9 activity in the bronchoalveolar lavage fluid. These findings suggest that ASP3258 has therapeutic potential for treating COPD not only through inhibition of pulmonary cellular accumulation but also by preventing lung structural alterations initiated by repeated cigarette smoke exposure. To our knowledge, this is the first paper demonstrating that PDE4 inhibitors exert significant inhibitory effects on subchronic cigarette smoke exposure-induced lung injury in guinea pigs.
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubo
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Intellectual Property, Astellas Pharma Inc., 2-3-11 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwata
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D006168:Guinea Pigs; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012906:Smoke / Q000009:adverse effects*; D013997:Time Factors; D014026:Nicotiana / Q000737:chemistry*
chemical_list: C561429:3-(4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid; D009287:Naphthyridines; D058988:Phosphodiesterase 4 Inhibitors; D012906:Smoke